Combined antiviral and antimediator treatment of common colds

ABSTRACT

The common cold is best treated by providing a combination of antiviral agents and antiinflammatory compounds to a patient infected with a cold virus. An antiviral agent and two antiinflammatory compounds given to a person infected with a cold virus simultaneously reduces the likelihood of a cold developing and the amount and duration of viral shedding, as well as substantially reduces the severity of individual cold symptoms and the overall number and severity of cold symptoms. Supplementing the activity of the combined antiviral and antiinflammatory agents with such compounds as antihistamines and alpha agonists results in suprisingly good nasal benefits. The combination therapy, termed COVAM therapy, is well tolerated and has no evidence of short-term toxicity.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of Ser. No. 07/794,520 filed Nov. 19,1991, now U.S. Pat. No. 5,240,694, which is a continuation in part ofSer. No. 07/764,004, filed Sep. 23, 1991, now abandoned. The disclosuresthereof are herein incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to the treatment of the commoncold and, more particularly, to a method and kit for cold treatmentwhich employs both antiviral and antimediator agents.

2. Description of the Prior Art

The "common cold" is a time honored phrase used by both physicians andlay persons alike for the identification of acute minor respiratoryillness. Since the discovery of rhinovirus in 1956, a considerable bodyof knowledge has been acquired on the etiology and epidemiology ofcommon colds. It is known that the common cold is not a single entity,but rather is a group of diseases caused by members of several familiesof viruses including parainfluenza viruses, rhinoviruses, respiratorysyncytial viruses, enteroviruses, and coronaviruses. Much work has beenperformed in characterizing viruses which cause the common cold. Inaddition, the molecular biology of rhinoviruses, the most importantcommon cold viruses, is understood in great detail. In contrast,progress on the treatment of common colds has been slow despite theseadvances. While there is now a large number of compounds which have beenfound to exhibit antiviral activity against cold viruses in cellculture, antiviral compounds have had limited effectiveness in patients.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide a method oftreating the common cold which utilizes both antiviral andantiinflammatory compounds.

It is another object of the invention to provide a method of treatingthe common cold which employs the simultaneous administration ofintranasal and oral medicants where the combination of medicationprovides both antiviral and antiinflammatory activity.

According to the invention, it was hypothesized that a major cause ofcommon cold symptoms is host inflammatory responses to infection inaddition to direct virus induced cytopathology. Experiments wereconducted which showed that the simultaneous administration of antiviraland antiinflammatory compounds to patients suffering a rhinovirusinduced cold had marketedly greater effect on treating the colds thanthe total cold combatting effects of each of the compounds takenseparately. The treatment involved the use of both intranasal and oralmedication. The treatment regimen is called "COVAM" therapy which is anacronym of combined virostatic (antiviral) antimediator therapy. Furtherexperiments have shown that combining COVAM therapy with additionalantimediators, such as by using alpha adrenergic agents andantihistamines in combination with the combined virostatic (antiviral)antimediator therapy, has dramatic benefits in a patient's subjectivecomplaints related to rhinorrhea and on the measured weights of expellednasal secretions.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, aspects and advantages will be betterunderstood from the following detailed description of a preferredembodiment of the invention with reference to the drawings, in which:

FIG. 1 is a graph showing the average measured viral titers for placeboand treated groups over a five day period of study;

FIG. 2 is a table slowing the viral shedding, antibody response, andillness occurrence for placebo and treated groups in two differentexperiments and the combined results of the two experiments;

FIG. 3 is a table showing the total and individual symptom scores ofrhinovirus infected subjects during two different experiments and thecombined results of the two experiments;

FIG. 4 is a graph showing the average measured mucus weights for treatedand placebo groups over a five day period of study with COVAM therapy;and

FIG. 5 is a graph showing the average measured mucus weights for treatedand placebo groups over a five day period of study when COVAM therapywas supplemented with an alpha adrenergic agent and an antihistamine.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

Investigations with human subjects have been conducted for a newtreatment for the common cold. In a first investigation, twenty eighthealthy adult volunteers with serum neutralizing antibody titers of lessthen or equal to 1:2 to an unnumbered rhinovirus, Hank's strain, wererecruited. As will be discussed below, the first investigation asconducted as two separate studies. In a second investigation, twentysubjects similar to those in the first investigation were used. In bothinvestigations, each of the subjects gave a written consent in a formapproved by the University of Virginia Human Investigation Committee.Subjects were excluded if they had a history of acute or chronicrespiratory illness, a history of sinusitis, allergic rhinitis, asthma,nasal polyps, alcoholism, or drug abuse; had used nasal decongestants orantiinflammatory drugs within twenty four hours, antihistamines withseventy two hours, or monoamine oxidase inhibitors, phenothiazines, ortopical or oral steroids within thirty days of initiation of the study.Persons with hypersensitivity to antiinflammatory drugs or severe drugallergy were also excluded, as were pregnant or lactating females. Onlysubjects who became infected with the challenge virus were included inthe investigations.

In both investigations, the virus challenge was an intranasallyadministered Hank's strain of rhinovirus. The virus was provided ascoarse drops in the form of two inocula (0.25 ml per nostril) givenapproximately ten minutes apart with the subject supine (laying down).Each subject was asked not to blow his/her nose for thirty minutes afterthe viral challenge. The viral inoculum contained a total of 30 TCID₅₀per volunteer, where TCID₅₀ defines the tissue culture infection dose ofvirus capable of infecting 50% of culture tubes in which it isinoculated.

The compounds selected for COVAM therapy each have different mechanismsof action and each have shown therapeutic activity when testedindividually in the rhinovirus challenge model. Commercially producedinterferon α-2, available from the Schering Corporation, withpre-packaged diluent (bacteriostatic water) was prepared in vials daily.The dosage was three million units three times a day, given in coarsedrops (0.1 ml per nostril). The diluent was used as the placebo in thefirst study of the first investigation and sterile physiologic salinewas used as the placebo for the second study of the first investigation.Ipratropium, which is commercially available from Boehringer-IngelheimCorporation, was provided in small pressurized canisters with attachedadapters for intranasal administration and was given at a dose of 80 μg(two puffs per nostril) three times a day. The placebo groups in the twostudies of the first investigation were given a nasal spray with inertpropellants in similar canisters. Naproxen, commercially available fromthe Syntex Corporation, was given in a dosage of a 500 mg loading dosefollowed thereafter by 250 mg three times a day. Similar appearingcapsules were administered to the placebo groups in the two studies ofthe first investigation. The presumed mechanisms of action of thecomponents in the combined treatment (COVAM therapy) are as follows:interferon α2 is perceived to have its major action in preventing viralreplication, ipratropium is an inhibitor of parasympathetic nervepathways, and naproxen is a propionic acid inhibitor of cylcooxygenasewhich is believed to exert its major effect on prostaglandins.

In the second investigation, the same antiinflammatory and antiviralcompounds were used (e.g., naproxen, ipratropium, and interferon α-2) inthe same dosages described above; however, the COVAM therapy wassupplemented with topical phenylephrine. HCl and chlorpheniramine.Phenylephrine. HCl is an alpha adrenergic agonist available from theSterling Drug company of New York and was added to the partially dilutedinterferon α-2 (described above for first investigation) to give a finalconcentration of 0.25% phenylephrine. Testing of this combination ofinterferon and phenylephrine in cell culture showed no loss ofrhinovirus inhibitory activity. Placebo nose drops were given as in thefirst investigation. Chlorpheniramine maleate is an antihistamine whichis given orally in tablet form and is available from Richlynlaboratories of Philadelphia. In the second investigation, opaquecapsules identical to those of naproxen which contained 4 mgchlorpheniramine maleate were administered with the naproxen. Subjectsin the second investigation received two placebo capsules which wereidentical to the capsules containing the naproxen and chlorpheniramine.

In both investigations, all medications were started twenty four hoursafter virus inoculation and continued for a total of four days. Dosingwas done at eight o'clock in the morning, four o'clock in the afternoon,and twelve midnight. Intranasal drops containing the interferon orinterferon plus phenylephrine were given with the subjects supine,followed by oral administration of the naproxen or naproxen andchlorpheniramine maleate, and then an intranasal spray of ipratropiumwas given with the subjects sitting.

As pointed out above, the first investigation was conducted as twoseparate studies, and the cohorts of subjects in each study were treatedthe same. The subjects were isolated in individual hotel rooms beginningtwelve hours after virus inoculation. The subjects were assigned toreceive either treatment or placebo and were blinded to their treatmentstatus, as was the observer recording all clinical information.Participants remained in the hotel until the fifth day after the viruschallenge. Following completion of the first study with the first cohortof volunteers, sample sizes were calculated for studying the secondcohort based on effect sizes observed with the first cohort. Power wascalculated under the assumption that findings in the first cohortrepresented true effects and that testing of the second cohort would beconducted at the α=0.05 level of significance. A power of ninety percentfor study days three and four was found to be obtainable with sevensubjects per group. The data were initially analyzed independently bycohort and then combined for final analysis. Viral titers, duration ofvirus shedding, symptom scores, and mucus weights were analyzed usingthe t test. Data comparing proportion were analyzed by Fisher's exacttest. All p-values are two tailed. Of the twenty eight subjects whichwere challenged with the virus, twenty five were "evaluable". Onesubject was excluded because he was infected with a wild strain ofrhinovirus before viral challenge, and two subjects did not becomeinfected with the challenge virus. Of the evaluable subjects, seventeenreceived treatment and eight received placebo. The mean age of personsreceiving drug treatment was 21.1 years and persons receiving placebowas 22.1 years. Of the evaluable subjects, ten males and seven femalesreceived drug treatment, and five males and three females receivedplacebo.

To monitor infection, nasal washes of each subject were collected priorto virus inoculation and once each morning. Washes were done by placing5 ml of saline in each nostril. After a ten second count, secretionswere expelled from both nostrils into a waxed paper container. Aftermixing in a syringe, portions of the nasal wash specimen weredistributed for testing and the remainder stored frozen in plastic vialsat -70° C. Washings were cultured for rhinovirus on human embryo lungfibroblast cells (WI-38) according to the procedures described inGwaltney et al., J. Infect. Dis., 142:811-815 (1980), which is hereinincorporated by reference. Three milliliters from each of the washes waspooled with one ml of viral collecting broth to prepare specimens forrhinovirus isolation and viral infectivity titers. One hundred-thirtymicroliters of antibody to interferon α2, which was purified by ammoniumsulfate precipitation, was added to one ml of viral collecting broth andthe mixture was added to all specimens from subjects which had receivedthe treatment to neutralize residual interferon activity which wouldinterfere with viral recovery.

FIGS. 1 and 2 present data obtained during the investigation whichprovide measures of infection for the cohorts of subjects in bothstudies. FIG. 1 presents the average measured viral titers of thetreated and placebo groups on each of the five days after inoculationwith the rhinovirus where the results of the cohorts of subjects forboth of the studies in the investigation have been combined. Viraltiters were determined by duplicate culture of serial tenfold dilutionsof once frozen and thawed nasal wash specimens. Titers were calculatedby the Karber method which is described in detail in Lennette et al.,Laboratory Diagnostics of Infectious Diseases, N.Y.: Springer-Verlag,1988, p.51, and which is herein incorporated by reference. Samples thatdid not grow virus were assigned a value of 0.5 log₁₀ TCID₅₀. FIG. 1shows that for the groups receiving COVAM therapy, the peak viral titeroccurred on the first day after viral challenge and thereafter declined.The trend corresponds with COVAM therapy beginning on the first dayafter inoculation. Conversely, the groups receiving placebo had a peakviral titer on the second day after viral challenge and the viral titersfor the placebo groups were significantly higher in the placebo group onthe second and third days than with the COVAM therapy treated groups.This indicates that COVAM therapy resulted in reduced viral replicationrelative to placebo, and that the natural history of the infectiousprocess had been reversed.

In the investigations, infection was defined as recovery of thechallenge virus from nasal washings on at least one day and/or afourfold or greater rise in serum neutralizing antibody to Hank's strainrhinovirus. Isolates were identified as Hank's strain rhinovirus byneutralization with type-specific antibody. According to the proceduresset forth in Gwaltney et al., Rhinovirus, Schmidt N.J., Emmons Rw eds.Diagnostic Procedures for Viral Rickettsial and Chlamydial Infections,6th ed., Wash. D.C.: American Public Health Association, 1989, p. 604.,which is herein incorporated by reference, sera were obtained in screwcapped tubes immediately prior to viral challenge and three weeks afterinoculation for measuring homotypic antibody to Hank's strainrhinovirus.

FIG. 2 shows that virus was recovered from seventeen of the subjects inthe groups receiving treatment and eight of subjects in the groupsreceiving placebo. As discussed above, the total number of subjects inthe investigation was twenty eight. Of those, nineteen subjects receivedtreatment, which corresponds to a eighty nine percent rate of infectionin the treatment group, and nine subjects received placebo, which alsocorresponds to an eighty nine percent rate of infection in the placebogroup. For the twenty five virus positive subjects, the mean duration ofvirus shedding, which is defined as the period during which virus wasrecovered by culture, was 4.4±0.3 days for the placebo group and 2.8±0.3days for the treatment group (p=0.003). The shortened period of time forshedding the virus was statistically significant.

FIG. 2 also shows that fourfold or greater serum neutralizing antibodyresponses occurred in eleven of seventeen (sixty five percent) and sixof eight (seventy five percent) of the subjects in the treatment andplacebo groups, respectively. Post-infection geometric mean antibodytiters were 6.8±4.8 and 8.8±6.0 in the treatment and placebo groups,respectively. The differences between the groups in the fraction whoseroconverted or in their post-infection geometric mean titers were notstatistically significant. This indicates that COVAM therapy had modestor no effect on the humoral immune response to rhinovirus infection.

FIGS. 2 and 3 show the number of colds and the occurrence and severityof symptoms, respectively, experienced by the subjects during theinvestigation according to a modified Jackson criteria (See, Jackson etal., Arch. Intern. Med., 101:267-78 (1958), which is herein incorporatedby reference, and Gwaltney et al, J. Infect. Dis., 142:811-815 (1980)).In brief, the occurrence and severity of symptoms were determined beforevirus challenge (day 0) and on each morning before the subject receivedthe combined drug treatment or the placebo on post-virus challenge daysone through five by a study nurse who recorded the subject's assessmentof the symptoms over the twenty four hour period on the followingfive-point scale: 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe.The symptoms assessed were runny nose, nasal stuffiness, sneezing, sorethroat, cough, headache, malaise, and chilliness. The total symptomsscore was determined by adding the symptoms during the five day period.The score for each individual symptom present before virus challenge(day 0) was subtracted from each of the daily scores for that symptom.Information was also recorded daily concerning the presence of any othersymptoms possibly related to drug toxicity.

FIG. 2 shows that colds, as judged by the modified Jackson criteria,developed in seven of seventeen (forty one percent) of the subjectswhich received treatment, while colds developed in seven of eight(eighty eight percent) of the subjects in the placebo groups (p=0.04).Diagnosis of a cold depended on a total symptom score of six or more andeither presence of rhinorrhea on three or more days or the subjectiveimpression of having had a cold. FIG. 3 shows that the mean totalsymptom score over the four days of treatment was 9.4±2.2 for thetreated subjects compared to a mean total symptom score of 24.9±2.8 forthe subjects in the placebo groups (p≦0.01). In agreement with the viraltiter data presented in FIG. 1, the daily mean total symptom score forthe subjects in the treatment groups increased slightly for the firstday of treatment (second day after inoculation), and thereafter declinedover the next three days to near the pre-illness value. Conversely, inthe placebo group, the daily mean total symptom score continued to rise,peaking on the second day of treatment (third day after inoculation).This beneficial effect was confirmed by generalized multivariateanalysis of variance which showed a 59% reduction in the average areaunder the four-day symptom curve for the treated group compared to theplacebo group (p=O. 004).

Scores for the individual symptoms over the four days of treatment werereduced in the treatment groups for all symptoms except sneezing andchilliness (although chilliness occurred infrequently in both groups).The difference observed were significant for rhinorrhea (p=0.08), nasalobstruction (p≦0.05), sore throat (p≦0.01), cough (p=0.05), headache(p=0.01), and malaise (p≦0.01). Part of the nasal obstruction scoresrecorded may have resulted from the physical effects of repetitiveintranasal spraying and dropping of medications. Also, sneezingfrequently accompanied installation of the drug or placebo. Sneezing isa somewhat dramatic symptom, but it does not substantially add to thetotal symptom score of rhinovirus colds.

FIG. 4 shows the mucus weights (nasal secretions) for the treatment andplacebo groups in both studies of the first investigation which weremeasured on a daily basis according to the method described in Doyle etal., Pediatr. Infect. Dis. J., 7:215-242 (1988), which is hereinincorporated by reference. Briefly, subjects collected used nasaltissues in air tight containers and the tissue collections were countedand weighed at 24 hour intervals with the weight of an equivalent numberof unused tissues subtracted from that of the tissues used by thevolunteers. The mean nasal mucous weights were only slightly lower inthe treated group (17.5±6.4 gm/four days) than the placebo group(20.3±5.4 gm/four days). One individual in the treatment group produceda total of 91 gm of mucus, which may have skewed the results of thetreatment group and placebo group closer together. The amount of mucusproduced by this subject places him in the 98th percentile for nasalmucus production based on a review of 14 experiments involving 151volunteers in Charlottesville using the rhinovirus challenge model. Inretrospect, this subject also gave a history of having allergic rhinitiswhich he did not provide in the intake history. When the values of thissubject were excluded from the analysis, the total mucus production overthe four days for the treatment group declined by twenty seven percentto 12.9±4.8 gm/four days as shown in FIG. 4.

After the first investigation was completed, the subjects were asked tojudge if they had been treated with the combination antiviralantimediator (COVAM) therapy or with placebo. Fourteen of the seventeenin the treatment group judged they had received drug COVAM, eight ofwhich said cold symptoms started and then subsided, and four of whichsaid that a cold never developed. Six out of eight subjects in theplacebo group judged they were on placebo, two of which said that theyhad no relief from the symptoms. In the group of seventeen subjectsreceiving treatment, there were four complaints of nasal stinging orburning, two complaints of nasal dryness, and one complaint each of mildepistaxis, muscle ache, "wakefulness", postnasal drip, and stomachcramps. In the group of eight subjects receiving placebo, there werethree complaints of stuffy ear or earache, two complaints of nasalstinging or burning, and one complaint each of nasal dryness and chestcongestion. All complaints were judged as mild and did not necessitateinterruption of administration of the treatment or placebo.

The results of the first investigation show that by using a combinationof an antiviral agent and two antiinflammatory compounds givensimultaneously by the intranasal or oral route it is possible to reducethe likelihood of a cold developing and the amount and duration of viralshedding, as well as substantially reduce the severity of individualcold symptoms and the overall number and severity of cold symptoms. Theeffectiveness of the COVAM therapy is believed to have resulted from thesimultaneous inhibition of viral replication and the blocking ofmediator activity due to virus already present in the nose at the timethat treatment was started. Once COVAM therapy had had time to exert itsfull effect, there was less virus produced in the nasal cells and themediator stimulating effect of virus which was produced was reduced orblocked. COVAM therapy was well tolerated and there was no evidence ofshort-term toxicity.

The second investigation was conducted to determine if any shortcomingsof COVAM therapy, such as nasal symptoms or the like, could compensatedfor by supplementing the antiinflammatory and antiviral compounds (e.g.,naproxen, ipratropium, and interferon) with an antihistamine or an alphaagonist. As discussed above, the alpha adrenergic agent phenylephrineand the antihistamine chlorpheniramine were administered with thenaproxen, irpratropium and interferon in the second investigation.

The second investigation was conducted in substantially the same manneras the first. However, a nasal wash was performed prior to viralchallenge but on no other days of the second investigation. Specimensfor viral culture were performed by having the volunteers expel nasalsecretions onto a plastic film as described in Naclerio et al., J.Infect. Dis., 157:133-42 (1988), which is herein incorporated byreference. This method was adopted to avoid possible irritation of thenasal passages by serial nasal washes. Twelve of the twentyvirus-challenged subjects in the second investigation were evaluable.Three subjects grew a wild strain of rhinovirus from the pre-inoculationculture, and the challenge virus was not recovered from five. The meanages were 21.9 and 22.6 in the treated and placebo groups, respectively.Three males and four females received the supplemented COVAM therapytreatment and one male and four females received placebo. Colds occurredin six of seven subjects in the treated group and in all five subjectsof the placebo group. The mean (±SEM) total symptom score for the fourdays of treatment was 27.6 (±8.0) in the placebo group and 16.3 (±4.2)for the treated group (p=0.2). The mean (±SEM) four-day rhinorrhea scorewas 3.8 (±1.6) in the placebo group and 0.9 (±0.6) in the treated group(p=0.08). Trends associating COVAM therapy with benefits in headache,malaise, chilliness, and cough were seen as in the first investigation,but sneezing, nasal obstruction and sore throat scores were similar inthe two groups. There was an increased incidence of sore throat in thetreated group in the second investigation relative to the treated groupin the first investigation; however, this may be due to the irritatingeffect of phenylephrine on the pharynx.

FIG. 5 shows that supplementing COVAM therapy with an alpha adrenergicagonist and an antihistamine had a marked effect on volume of nasalsecretions produced. The mean (±SEM) four day total of nasal secretionswas 22.2 (±12.9) gm for the five subjects in the placebo group and 1.6(±0.6) gm for the seven subjects in the treated group (p=0.8); aremarkable 90% reduction.

Six of the seven subjects in the supplemented COVAM therapy treatedgroup reported that cold symptoms were milder and did not develop asexpected and three specifically mentioned the paucity of nasalsecretions. Of the ten subjected receiving treatment, one reporteddrowsiness, one reported feeling tired, one reported burning in thenose, and one reported itching of the eyes. Of the ten subjectsreceiving placebo, two reported nasal burning, one nasal dryness, onenausea, and one drowsiness. The dramatic effects seen in the subjectivecomplaints of rhinorrhea and on the measured weights of expelled nasalsecretions may be due in part to the vasoconstrictive action ofphenylephrine in reducing transudation of intravascular fluid in thenasal passages. Also, chlorpheniramine may have blocked some action oractions of histamine which play a role in stimulating the production ofnasal secretions.

The rhinovirus challenge model used in this investigation has been usedbefore to evaluate each of the individual components of the combinedtreatment taken alone. Specifically, Hayden et al., J. Infect. Dis.,150:174-80 (1984) describes the intranasal interferon α2 treatment ofrhinovirus colds and Gaffey et al., Antimicrob. Agents Chemother.,32:1644-7 (1988) describes the ipratropium bromide treatment ofexperimental rhinovirus infection, and both of these articles areincorporated by reference. In addition, an article by Sperber et al., onwhich the inventor of this invention is noted as an author, has beensubmitted to Annls. Int. Med. and it describes the beneficial effects ofnaproxen in experimental rhinovirus colds. In the naproxen study of thesubmitted article, 39 patients received naproxen at a loading dose ofeither 400 or 500 mg. followed by either 200 or 500 mg of naproxen threetimes a day for five days where treatment began 6 hours after viruschallenge. The experimental design was similar and the methods ofevaluation and symptom scoring reported in each of the articles wasidentical to that used in the present investigation. In the ipratropiumstudy, there was no difference in the mean total symptom scores duringfour days of treatment (ipratropium group 10±1.6; placebo/control group9.5±1.2), although ipratropiumhad a mild beneficial effect on nasalsymptoms and nasal mucus production. In the interferon study, the meantotal symptoms score during four days of treatment (13.4±1.6) wasslightly lower than the score for the placebo/control group (15.1±2.4),but the difference was not significant. Interferon treated subjects alsohad less nasal symptoms and nasal mucus production than controls. In thenaproxen study, the mean total symptoms score for the naproxen groupduring the four days of treatment (12±1.65) was thirty four percentlower than that for the group receiving placebo (17.35±2.6)(p=0.08). Inthe naproxen study, headache, malais, myalgia, and cough weresignificantly reduced in the treated group.

Comparing these results with those obtained for COVAM therapy, themagnitude of improvement in the mean total symptom score for the groupreceiving the COVAM treatment (fifty nine percent for firstinvestigation) was considerably greater than that seen when the resultswith individual treatments are combined, suggesting that the COVAMtherapy had a synergistic effect in reducing symptoms of experimentalrhinovirus colds. As pointed out above, this improvement ineffectiveness is believed to have resulted from the simultaneousinhibition of viral growth and the blocking of mediator activity whichwas occurring because of virus already present in the nose. Once COVAMtherapy began to exert its full effect, there was less virus produced inthe nasal cells and the mediator stimulating effect of any virus whichwas produced was reduced or blocked. The second investigation showedthat supplementing COVAM therapy can have dramatic effects in terms ofsubjective complaints of rhinorrhea and nasal secretion production. Theeffectiveness of the COVAM therapy is also greater than that reportedfor a number of other treatments of experimental rhinovirus colds (See,Phillpotts et al., Lancet, 1:1342-44 (1981), Phillpotts et al.,Antimicrob. Agents Chemother., 23:671-75 (1983) , Al-Nakib et al., J.Antimicrob. Chemother., 20:893-901 (1987), Farr et al., Antimicrob.Agents Chemother., 31:1183-87 (1987), Al-Nakib et al., Antimicrob.Agents Chemother., 33:522-5 (1989) , Hayden et al., Antiviral Res.233-47 (1988), Gaffey et al., Amer. Rev. Respit. Dis., 136:556-60(1987), Sperber et al., Bull NY Acad. Med., 65:145-60 (1989), and Farret al., J. Infect. Dis., 162:1173-7 (1990)). The benefits of the COVAMtherapy and supplemented COVAM therapy also appears to be superior toavailable commercial cold remedies based on the known mechanism ofaction of the ingredients in those remedies.

While the antiviral agent used in the investigations was inteferon α2,other antiviral agents which are specific for viruses commonly found incolds should yield the same synergistic cold combatting results whenused in combination with antiinflammatory compounds. As suitableexamples of antiviral agents that could be used in COVAM therapy,Sperber et al., Antimicrob. Agents Chemother., 32:409-419 (1988), whichis herein incorporated by reference, provides a listing ofrepresentative antiviral agents with activity against rhinovirus whichincludes the following: Inteferons (rIFN-α_(2b), rIFN-α_(2a),rIFN-β_(serine)), Interferon inducers (Poly I:C, N,N-Dioactadecyl-N',N'-bis-(2-hydroxyethyl)-propanediamine (CP-20,961), Capsid bindingagents/inhibitors of uncoating (4',6-Dichloroflavan (BW 683C),4'-ethoxy-2'-hydroxy-4,6'-dimethoxychalcone (Ro 09-0410),5-ethoxy-3-methoxy-2-(p-methoxy-trans-cinnamoyl)phenylphosphate (Ro09-0415), 1-(5-tetradecyloxy-2-furanyl)ethanone (RMI 15,731),2-[-(1,5,10,10a-tetrahydro-3H-thiazolo[3,4b]isoquinolin-3-ylindene)amino]-4-thiazoleacetic acid (44,081 R.P.), Disoxaril, 5-[7-[ 4-(4,5dihydro-2-oxazolyl)phenoxy]heptyl]-3-methylisoxazole (WIN 51,711),3-methoxy-6-[4-(3-methylphenyl)-piperazinly]pyradazine (R61837),3,4-dihydro-2-phenyl-2H-pyrano[2,3-b]pyridines, andphenoxypyridinecarbonitriles),2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL 860), Benzoimidazoles(Enviroxime, 2-amino-l-(isopropyl sulfonyl)-6-benzimidazole phenylketone oxime), 1'-methyl spiro(adamantane-2,3-pyrrolidine)maleate,Isatin thiosemicarbazone, Fusidic acid, Substituted trizainoindoles(4-([8-amino-7-chloro-5-methyl-5H-as-triazino(5,6-b)indol-3-yl]amino)-2-methyl-2-butanol (SK&F 40491)),2,6-diphenyl-3-methyl-2,3-dihydroimidazo[2,1-b]thiazole (RP 19236),3-alpha-naphthl-5-diethylcarbamoyl-1,2,4,-oxadiazole (GL R9-338),Oxolinic acid, Isoquinolines(1-(p-chlorophenoxymethyl)-3,4-dihydroisoquinone hydrochloride(UK-2054), 3,4-dihydro-1-isoquinolineacetamide hydrochloride),1-p-chlorophenyl-3-(m-3-isobutyl-guanidinophenyl)urea hydrochloride (ICI73,602), and Zinc salts. Substances which prevent attachment of therhinovirus to the nasal cells, such as anti ICAM-1 antibody [Hayden etal, Antiviral Res., 9:233-247 (1988)]and synthetic ICAM-1 [Greve et al.,Cell, 56:839-847 (1989)], and other types of interferon should also beuseful in COVAM therapy. In addition, agents which are known to beeffective against influenza virus, another respiratory virus, such asamantadine, rimantadine, and ribavirin will be useful in COVAM therapy,as well as, antiviral agents which may become available to treat othercold viruses including coronavirus, parainfluenza virus, rhinovirus,adenovirus, influenza virus, and respiratory syncytial virus.

While the antiinflammatory compounds used in the investigations wereipratropium, naproxen, phenylephrine, and chlorpheniramine, otherantiinflammatory compounds could be substituted or added within thepractice of the invention. For example, it has been found that blockingcold symptoms can be accomplished by administering compounds which havetheir pharmacologic activity from blocking or inhibiting specificpathways of inflammation. Specifically, this has been shown withatropine methonitrate [See, Gaffey et al., Amer. Rev. Respir. Dis.,135:241-244 (1987)] and ipratropium [See, Gaffey et al., Antimicrob.Agents Chemother., 32:1644-1647 (1988)]for the parasympathetic pathwaysof inflammation, with intranasal and systemic glucocorticoid steroids[See, Farr et al., J. Infect. Dis., 162:1173-1177 (1990)] forarachidonic acid metabolites, and with chlorpheniramine [See, Doyle etal., Pediatr. Infect. Dis. J., 7:229-238 (1988)]for histamine. All ofthe above compounds, as well as others which block, antagonize, orotherwise inhibit pathways of inflammation associated with the varioussigns and symptoms of acute respiratory disease would be expected toperform well in COVAM therapy.

Because the human immune system appears to have considerable redundancyin the pathways and mechanisms which are capable of stimulatinginflammation, it is believed to be necessary to block multiple pathwaysin order to maximize the clinical effectiveness of the COVAM treatment.In the nose, there is evidence that at least seven pathways have a rolein the production of signs and symptoms of illness during rhinovirusinfection or natural colds. These pathways and mechanisms include theparasympathetic nervous systems [See, Gaffey et al., Amer. Rev. Respir.Dis., 135:241-244 (1987) and Gaffey et al., Antimiro. Agents Chemother.,32:1644-1647 (1988)], the kinin (bradykinin and lysylbradykinin) pathway[See, Naclerio et al., J. Infect. Dis., 161:120-123 (1990) and Proud etal., J. Infect. Dis., 7:229-238 (1988)], the histamine pathway [See,Doyle et al., Pediatr. Infect. Dis. J., 7:229-238 (1988)], theinterleukin-1 pathway [personal communication, Gwaltney], the alphaadrenergic pathway as shown by long established effectiveness of alphaadrenergic agonists (phenylepherine and pseudoephedrine), themetabolites of the cyclooxygenase pathway (the prostaglandins,etc.)[See, Farr et al., J. Infect. Dis., 162:1173-1177 (1990) as well asthe Sperber et al. experiments with naproxen discussed above], and theexogenous opioid agonists [See, Diehl, J. Amer. Med. Assoc.,101:2042-2049 (1933)]. Other nonsteroidal antiinflammatory agents likenaproxen, such as ibuprophen, should also be useful in COVAM therapy. Inaddition, there are other related and unrelated mechanisms ofinflammation production which have not been investigated for colds, butwhich may also play a role in their pathogenesis including themetabolites of the lipoxygenase pathway (leukotrienes, etc.), the otherinterleukins, and the processes controlling intracellular calcium fluxeswhich are inhibited by the calcium channel blockers.

While the alpha agonist used in the second investigation wasphenylephrine, other agonists could be substituted or added within thepractice of the invention. For example, pseudoephedrine,phenylpropanolamine, oxymetazoline, and xylometazoline are exemplarycompounds.

While the antihistamine used in the second investigation waschlorpheniramine, other agonists could be substituted or added withinthe practice of the invention. For example, diphenylhydramine,brompheniramine, clemastine, and terfenadine are exemplary compounds.

The total dosage used of the antiinflammatory and antiviral compounds inthe first and second investigations were as follows: ipratropium=960 μg,interferon α2=36 million units, and naproxen=3.25 gm. The total dosageused of the supplementing compounds in the second investigation were asfollows: phenylephrine=0.25% three times a day for four days, andchlorpheniramine=48 mg. The doses of compounds used in theinvestigations described were standard for adults with the exception ofinterferon α2, for which an optimal dose for treatment of colds has notbeen determined. Smaller doses may be possible while still retaining asatisfactory level of effectiveness. Dose levels for children would needadjustment to provide equivalence in effectiveness and safety to that ofadult doses.

To provide ease of use for the patient and to optimize compliance,medications may be provided in a prepackaged kit containing bothantiviral agents and antiinflammatory agents. The kit may contain aspray or dropper device for intranasal delivery of metered doses ofcombined medications for intranasal use and a blister pack containingpremeasured doses of pills, capsules, caplets, etc., containing combinedoral medications. Oral medications may also be given in combination withpharmacological binders, syrups, elixirs, and the like.

It is contemplated that a particularly good way of administering thedrugs required for COVAM therapy or supplemented COVAM therapysimultaneously would be to package appropriate quantities of each in ametered dose inhaler (MDI) such that they may be delivered as an aerosolfor inhalation. MIDIs have become a well accepted method of deliveringbronchodilators (B₂ agonists and anticholinergics), corticosteroids, andanti-allergics, and it is envisioned that inhalation would also be aviable means of delivering the types of compounds described above. FIDIscomprise a pressure resistant container typically filled with a productsuch as a drug dissolved in a liquified propellant or micronizedparticles suspended in a liquified propellant where the container isfitted with a metering valve. Actuation of the metering valve allows asmall portion of the spray product to be released whereby the pressureof the liquified propellant carries the dissolved or micronized drugparticles out of the container to the patient. The valve actuator isused to direct the aerosol spray into the patient's airway (upper andlower). Surfactants are usually dissolved in the spray product and canserve the dual functions of lubricating the valve and reducingaggregation of micronized particles. Commonly used surfactants includeoleic acid and sorbitan trioleate. The envisioned MDI could employ thecommonly used chlorofluorocarbons (CFCs) such as CCl₃ F (Freon 11 orCFC-11), CCl₂ F₂ (Freon 12 or CFC-12), and CClF₂ -CClF₂ (Freon 114 orCFC-114), or some combination thereof, as the propellant. Alternatively,non-ozone depleting propellants such as hydrocarbons (propane, butane,etc.), dimethyl ether, carbon dioxide, 1,1,1,2-tetrafluoroethane(HFC-134a), and combinations thereof, or limited ozone depletingpropellants such as HCFCs, and combinations thereof, could be employedas the propellant.

While the invention has been described in terms of its preferredembodiments, those skilled in the art will recognize that the inventioncan be practiced with considerable modification within the spirit andscope of the appended claims.

Having thus described my invention, what I claim as new and desire tosecure by Letters Patent is as follows:
 1. A kit for combatting thecommon cold, comprising:a therapeutically effective amount of at leastone antiviral agent specific for a virus which causes the common coldselected from the group consisting of rhinoviruses, adenoviruses,enteroviruses, coronaviruses, respiratory syncytial viruses, influenzaviruses and parainfluenza viruses; and a therapeutically effectiveamount of at least one antiinflammatory compound specific forinflammatory pathways of the common cold selected from the groupconsisting of the parasympathetic pathway, the cyclooxygenase andlipoxygenase pathways, the histamine pathway, the alpha adrenergicpathway, the interleukin-1 pathway, and the kinin pathway.
 2. A kit asrecited in claim 1 wherein said antinflammatory compound is selectedfrom the group consisting of ipratropium, atropine methonitrate,exogenous opioid agonists, alpha adrenergic agonists, antihistaminesincluding chlorpheniramine, prostaglandin blockers and antagonists,leukotriene blockers and antagonists, parasympathetic blockers andantagonists, interleukin blockers and antagonists, and nonsteroidalantiinflammatory agents including naproxen ibuprophen.
 3. A kit asrecited in claim 1 wherein said antiviral agent is selected from thegroup consisting of inteferons, interferon inducers, capsid bindingagents, benzoimidazoles, 1'-methylspiro(adamantane-2,3-pyrrolidine)maleate, isatin thiosemicarbazone,fusidic acid, substituted trizainoindoles,2,6-diphenyl-3-methyl-2,3-dihydroimidazothiazole,3-alpha-naphthl-5-diethylcarbamoyl-1,2,4-oxadiazole, oxolinic acid,isoquinolines, 1-p-chlorophenyl-3-(m-3-isobutylguanidinophenyl)ureahydrochloride, anti ICAM-1 antibody and other viral receptor antibodies,synthetic ICA-1 and other synthetic viral receptors, amantadine,rimantadine, and ribavirin.
 4. A kit as recited in claim 1 furthercomprising a therapeutically effective amount of at least oneantihistamine compound which is different from said antiinflammatorycompound.
 5. A kit as recited in claim 4 wherein said antihistamine isselected from the group consisting of chlorpheniramine,diphenylhydramine, brompheniramine, clemastine, and terfenadine.
 6. Amethod as recited in claim 1 further comprising a therapeuticallyeffective amount of at least one alpha agonist compound which isdifferent from said antiinflammatory compound.
 7. A kit as recited inclaim 6 wherein said alpha agonist is selected from the group consistingof phenylephrine, pseudoephedrine, phenylpropanolamine, oxymetazoline,and xylometazoline.
 8. A kit for combatting the common cold,comprising:a therapeutically effective amount of at least one antiviralagent specific for a virus which causes the common cold selected fromthe group consisting of rhinoviruses, adenoviruses, enteroviruses,coronaviruses, respiratory syncytial viruses, influenza viruses andparainfluenza viruses; and a therapeutically effective amount of atleast two antiinflammatory compounds specific for at least two differentinflammatory pathways of the common cold selected from the groupconsisting of the parasympathetic pathway, the cyclooxygenase andlipoxygenase pathways, the histamine pathway, the alpha adrenergicpathway, the interleukin-1 pathway, and the kinin pathway.
 9. A kit asrecited in claim 8 wherein said antiviral agent is interferon α2, andwherein said antiinflammatory agents include naproxen and ipratropium.10. A kit as recited in claim 8 wherein at least one of said antiviralagent and said antiinflammatory compounds is present in orallydeliverable form and at least one of said antiviral agent and saidantiinflammatory compounds is present in nasally deliverable form.
 11. Akit as recited in claim 8 wherein said antinflammatory compounds areselected from the group consisting of ipratropium, atropinemethonitrate, exogenous opioid agonists, alpha adrenergic agonists,antihistamines including chlorpheniramine, prostaglandin blockers andantagonists, leukotriene blockers and antagonists, parasympatheticblockers and antagonists, interleukin blockers and antagonists, andnonsteroidal antiinflammatory agents including naproxen and ibuprophen.12. A kit as recited in claim 8 wherein said antiviral agent is selectedfrom the group consisting of inteferons, interferon inducers, capsidbinding agents, benzoimidazoles, 1'-methylspiro(adamantane-2,3-pyrrolidine)maleate, isatin thiosemicarbazone,fusidic acid, substituted trizainoindoles,2,6-diphenyl-3-methyl-2,3-dihydroimidazo[2,1-b]thiazole,3-alpha-naphthl-5-diethylcarbamoyl-1,2,4-oxadiazole, oxolinic acid,isoquinolines, 1-p-chlorophenyl-3-(m-3-isobutylguanidinophenyl)ureahydrochloride, anti ICAM-1 antibody and other viral receptor antibodies,synthetic ICAM-1 and other synthetic viral receptors, amantadine,rimantadine, and ribavirin.
 13. A kit as recited in claim 8 furthercomprising a therapeutically effective amount of at least oneantihistamine which is different from said antiinflammatory compound.